Chromosomal rearrangements of the receptor tyrosine kinase ROS1 are oncogenic drivers in multiple malignancies (Davare M A and Tognon C E, Biol Cell 107, 111-129 (2015); incorporated by reference herein). Fusion of the intact ROS1 tyrosine kinase domain with various gene partners results in constitutive activation of downstream pathways responsible for tumor growth and proliferation. In lung adenocarcinomas, ROS1 rearrangements comprise a distinct molecular subset of tumors present in 1-2% of patients. CD74-ROS1 is the most common fusion in this context (Rimkunas V M et al, Clin Cancer res 18, 4449-4457 (2012); Takeuchi K et al, Nat Med 18, 378-381 (2012); and Bergethon K et al, J Clin Oncol 30, 863-870 (2012); all of which are incorporated by reference herein).
ROS1-rearranged lung cancers are highly sensitive to treatment with the ROS1/ALK tyrosine kinase inhibitor (TKI) crizotinib (Mazieres J et al, J Clin Oncol 33, 992-999 (2015); incorporated by reference herein), with a response rate of 72% and a median progression-free survival of 19 months based on phase 1 expansion cohort data (Shaw A T et al, N Engl J Med 371, 1963-1971 (2014); incorporated by reference herein). Consistent with the experience with crizotinib in the treatment of advanced ALK-rearranged lung cancers, acquired resistance has also begun to emerge in patients harboring ROS1 fusions Awad M M et al, N Engl J Med 368, 2395-2401 (2013); incorporated by reference herein), although the scope of such resistance mechanisms in this setting remain unknown. Second-generation ROS1 inhibitors are in clinical development and may provide viable treatment options for patients with resistance to crizotinib, but clinical response to these agents has not been published to date.